Purpose: To investigate the underlying mechanism of low bioavailabilities of the water-soluble camptothecin derivatives, belotecan and topotecan.
Methods: The bioavailability of belotecan and topotecan in rats was determined following oral administration of each drug at a dose of 5 mg/kg body weight. The vectorial transport of each drug was measured in Caco-2 and engineered MDCK II cells.
Results: The bioavailability of belotecan (11.4%) and topotecan (32.0%) in rats was increased to 61.5% and 40.8%, respectively, by the preadministration of CsA at a dose of 40 mg/kg. Contrary to the absorptive transport, the secretory transport of these drugs across the Caco-2 cell monolayer was concentration-dependent, saturable, and significantly inhibited by the cis presence of verapamil (a P-gp substrate), MK-571 (an MRP inhibitor), bromosulfophthalein (BSP, an MRP2 inhibitor), fumitremorgin C (FTC, a BCRP inhibitor) and cyclosporine A (CsA, an inhibitor of P-gp and BCRP, and a substrate of P-gp) suggesting the involvement of these transporters, which could be further confirmed in MDCKII/P-gp, MDCKII/MRP2 and MDCKII/BCRP cells.
Conclusion: The involvement of secretory transporters P-gp, MRP2 and BCRP, particularly for belotecan, as well as a low passive permeability, appears to be responsible for the low bioavailability of belotecan and topotecan.